Corey Lyon, DO

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk for anti-D antibodies, placing the fetus at risk for hemolytic disease of the fetus and newborn (HDFN). If undiagnosed and/or untreated, HDFN carries significant risk for perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk for maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk for fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 137) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimesters calculated a sensitivity of 99.3% and a specificity of 98.4%.⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Continue to: STUDY SUMMARY

Test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 µg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and nine false-negative results. In the nine false negatives, six were due to a lack of fetal DNA in the sample and three were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

Continue to: WHAT'S NEW

Accurate test, potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

CAVEATS

Different results by ethnicity?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D immunoglobulin prophylaxis would be different in the United States than in other countries.

Also, in this study, polymerase chain reaction for two RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[5]: 306, 308, 319).

EVIDENCE SUMMARY

A randomized, placebo-controlled trial including 1142 patients with COPD (forced expiratory volume in one second [FEV₁] <70%, postbronchodilator FEV₁ <80%) found that daily azithromycin 250 mg reduced acute exacerbations more than placebo over one year.¹ Researchers recruited patients who were using supplemental oxygen, had required glucocorticoids, or had been hospitalized for an acute exacerbation in the last year. Patients with asthma, resting heart rate >100 beats/min, prolonged QTc interval (or on prolonging medications), or hearing impairment were excluded.

Azithromycin increased the median time to first exacerbation (defined as increase or new onset of cough, sputum, wheeze, and chest tightness for 3 days requiring antibiotics or systemic steroids) compared with the placebo group (266 days vs 174 days; P<.001) and reduced the risk of an acute exacerbation per patient year (hazard ratio [HR]=0.73; 95% confidence [CI], 0.63-0.84). It also reduced the rate of acute exacerbations per patient year (1.83 vs 1.43; P=.01; rate ratio=0.83; 95% CI, 0.72-0.95). The number needed to treat to prevent one exacerbation was 2.86.

No differences in death from any cause (3% vs 4%; P=.87), death from respiratory cause (2% vs 1%; P=.48), or death from cardiovascular cause (0.2% vs 0.2%; P=1.0) were found between azithromycin and placebo. Nor did rates of hospitalizations for acute exacerbations differ.

The groups also showed no significant difference in serious adverse events leading to discontinuation of medication. Notably, more patients in the azithromycin group had audiogram-confirmed hearing loss (25% vs 20%; P=.04), although the authors state that their criteria for hearing loss may have been too stringent because hearing improved on repeat testing whether or not the study drug was discontinued. In addition, more patients in the placebo group developed nasopharyngeal colonization with methicillin-resistant Staphylococcus aureus (31% vs 12%; P<.001).

Older ex-smokers on long-term O₂ benefit most from the antibiotic

A retrospective subgroup analysis of the RCT identified patients who benefited most from daily azithromycin therapy.² Compared with placebo, azithromycin decreased the time to first exacerbation in patients >65 years (542 patients; HR=0.59; 95% CI, 0.47-0.74), but not patients ≤65 years (571 patients; HR=0.84; 95% CI, 0.68-1.04).

The azithromycin group also demonstrated decreased time to first exacerbation in ex-smokers (867 patients; HR=0.65; 95% CI, 0.55-0.77) and patients on long-term oxygen (659 patients; HR=0.66; 95% CI, 0.55-0.80) but not current smokers (246 patients; HR=0.99; 95% CI, 0.71-1.38) or patients not using long-term oxygen (454 patients; HR=0.80; 95% CI, 0.62-1.03).

Azithromycin administration decreased exacerbations in patients with GOLD stages II (292 patients; HR=0.55; 95% CI, 0.40-0.75) and III (451 patients; HR=0.71; 95% CI, 0.56-0.90), but not stage IV (370 patients; HR=0.84; 95% CI, 0.65-1.08). The significance of the results is limited because the study was not originally powered for this level of subgroup analysis.

Continue to: Smaller study shows similar results

A smaller RCT of 92 patients that evaluated exacerbation rates with azithromycin and placebo recruited patients with at least 3 acute COPD exacerbations in the previous year.³

Compared with placebo, oral azithromycin 500 mg 3 times a week (Monday, Wednesday, and Friday) increased the time between exacerbations over a 12-month period (59 days vs 130 days; P=.001). It also reduced the exacerbation rate per person per year (1.94 vs 3.22; risk ratio=0.60; 95% CI, 0.43-0.84) but didn’t change the hospitalization rate (odds ratio=1.34; 95% CI, 0.67-2.7).

No difference in serious adverse events was found between the azithromycin and placebo groups (3 patients vs 5 patients; P=NS), but an increase in diarrhea (9 patients vs 1 patient; P=.015) was noted.

RECOMMENDATIONS

An evidence-based guideline by the American College of Chest Physicians and Canadian Thoracic Society recommends long-term macrolide therapy to prevent acute exacerbations in patients >40 years with moderate or severe COPD and a history of ≥1 moderate or severe exacerbation in the previous year despite maximized inhaler therapy (Grade 2A, weak recommendation, high-quality evidence).⁴ The guideline also states that the duration and optimal dosages are unknown.

EVIDENCE SUMMARY

A randomized, placebo-controlled trial including 1142 patients with COPD (forced expiratory volume in one second [FEV₁] <70%, postbronchodilator FEV₁ <80%) found that daily azithromycin 250 mg reduced acute exacerbations more than placebo over one year.¹ Researchers recruited patients who were using supplemental oxygen, had required glucocorticoids, or had been hospitalized for an acute exacerbation in the last year. Patients with asthma, resting heart rate >100 beats/min, prolonged QTc interval (or on prolonging medications), or hearing impairment were excluded.

Azithromycin increased the median time to first exacerbation (defined as increase or new onset of cough, sputum, wheeze, and chest tightness for 3 days requiring antibiotics or systemic steroids) compared with the placebo group (266 days vs 174 days; P<.001) and reduced the risk of an acute exacerbation per patient year (hazard ratio [HR]=0.73; 95% confidence [CI], 0.63-0.84). It also reduced the rate of acute exacerbations per patient year (1.83 vs 1.43; P=.01; rate ratio=0.83; 95% CI, 0.72-0.95). The number needed to treat to prevent one exacerbation was 2.86.

No differences in death from any cause (3% vs 4%; P=.87), death from respiratory cause (2% vs 1%; P=.48), or death from cardiovascular cause (0.2% vs 0.2%; P=1.0) were found between azithromycin and placebo. Nor did rates of hospitalizations for acute exacerbations differ.

The groups also showed no significant difference in serious adverse events leading to discontinuation of medication. Notably, more patients in the azithromycin group had audiogram-confirmed hearing loss (25% vs 20%; P=.04), although the authors state that their criteria for hearing loss may have been too stringent because hearing improved on repeat testing whether or not the study drug was discontinued. In addition, more patients in the placebo group developed nasopharyngeal colonization with methicillin-resistant Staphylococcus aureus (31% vs 12%; P<.001).

Older ex-smokers on long-term O₂ benefit most from the antibiotic

A retrospective subgroup analysis of the RCT identified patients who benefited most from daily azithromycin therapy.² Compared with placebo, azithromycin decreased the time to first exacerbation in patients >65 years (542 patients; HR=0.59; 95% CI, 0.47-0.74), but not patients ≤65 years (571 patients; HR=0.84; 95% CI, 0.68-1.04).

The azithromycin group also demonstrated decreased time to first exacerbation in ex-smokers (867 patients; HR=0.65; 95% CI, 0.55-0.77) and patients on long-term oxygen (659 patients; HR=0.66; 95% CI, 0.55-0.80) but not current smokers (246 patients; HR=0.99; 95% CI, 0.71-1.38) or patients not using long-term oxygen (454 patients; HR=0.80; 95% CI, 0.62-1.03).

Azithromycin administration decreased exacerbations in patients with GOLD stages II (292 patients; HR=0.55; 95% CI, 0.40-0.75) and III (451 patients; HR=0.71; 95% CI, 0.56-0.90), but not stage IV (370 patients; HR=0.84; 95% CI, 0.65-1.08). The significance of the results is limited because the study was not originally powered for this level of subgroup analysis.

Continue to: Smaller study shows similar results

A smaller RCT of 92 patients that evaluated exacerbation rates with azithromycin and placebo recruited patients with at least 3 acute COPD exacerbations in the previous year.³

Compared with placebo, oral azithromycin 500 mg 3 times a week (Monday, Wednesday, and Friday) increased the time between exacerbations over a 12-month period (59 days vs 130 days; P=.001). It also reduced the exacerbation rate per person per year (1.94 vs 3.22; risk ratio=0.60; 95% CI, 0.43-0.84) but didn’t change the hospitalization rate (odds ratio=1.34; 95% CI, 0.67-2.7).

No difference in serious adverse events was found between the azithromycin and placebo groups (3 patients vs 5 patients; P=NS), but an increase in diarrhea (9 patients vs 1 patient; P=.015) was noted.

RECOMMENDATIONS

An evidence-based guideline by the American College of Chest Physicians and Canadian Thoracic Society recommends long-term macrolide therapy to prevent acute exacerbations in patients >40 years with moderate or severe COPD and a history of ≥1 moderate or severe exacerbation in the previous year despite maximized inhaler therapy (Grade 2A, weak recommendation, high-quality evidence).⁴ The guideline also states that the duration and optimal dosages are unknown.

EVIDENCE SUMMARY

A randomized, placebo-controlled trial including 1142 patients with COPD (forced expiratory volume in one second [FEV₁] <70%, postbronchodilator FEV₁ <80%) found that daily azithromycin 250 mg reduced acute exacerbations more than placebo over one year.¹ Researchers recruited patients who were using supplemental oxygen, had required glucocorticoids, or had been hospitalized for an acute exacerbation in the last year. Patients with asthma, resting heart rate >100 beats/min, prolonged QTc interval (or on prolonging medications), or hearing impairment were excluded.

Azithromycin increased the median time to first exacerbation (defined as increase or new onset of cough, sputum, wheeze, and chest tightness for 3 days requiring antibiotics or systemic steroids) compared with the placebo group (266 days vs 174 days; P<.001) and reduced the risk of an acute exacerbation per patient year (hazard ratio [HR]=0.73; 95% confidence [CI], 0.63-0.84). It also reduced the rate of acute exacerbations per patient year (1.83 vs 1.43; P=.01; rate ratio=0.83; 95% CI, 0.72-0.95). The number needed to treat to prevent one exacerbation was 2.86.

No differences in death from any cause (3% vs 4%; P=.87), death from respiratory cause (2% vs 1%; P=.48), or death from cardiovascular cause (0.2% vs 0.2%; P=1.0) were found between azithromycin and placebo. Nor did rates of hospitalizations for acute exacerbations differ.

The groups also showed no significant difference in serious adverse events leading to discontinuation of medication. Notably, more patients in the azithromycin group had audiogram-confirmed hearing loss (25% vs 20%; P=.04), although the authors state that their criteria for hearing loss may have been too stringent because hearing improved on repeat testing whether or not the study drug was discontinued. In addition, more patients in the placebo group developed nasopharyngeal colonization with methicillin-resistant Staphylococcus aureus (31% vs 12%; P<.001).

Older ex-smokers on long-term O₂ benefit most from the antibiotic

A retrospective subgroup analysis of the RCT identified patients who benefited most from daily azithromycin therapy.² Compared with placebo, azithromycin decreased the time to first exacerbation in patients >65 years (542 patients; HR=0.59; 95% CI, 0.47-0.74), but not patients ≤65 years (571 patients; HR=0.84; 95% CI, 0.68-1.04).

The azithromycin group also demonstrated decreased time to first exacerbation in ex-smokers (867 patients; HR=0.65; 95% CI, 0.55-0.77) and patients on long-term oxygen (659 patients; HR=0.66; 95% CI, 0.55-0.80) but not current smokers (246 patients; HR=0.99; 95% CI, 0.71-1.38) or patients not using long-term oxygen (454 patients; HR=0.80; 95% CI, 0.62-1.03).

Azithromycin administration decreased exacerbations in patients with GOLD stages II (292 patients; HR=0.55; 95% CI, 0.40-0.75) and III (451 patients; HR=0.71; 95% CI, 0.56-0.90), but not stage IV (370 patients; HR=0.84; 95% CI, 0.65-1.08). The significance of the results is limited because the study was not originally powered for this level of subgroup analysis.

Continue to: Smaller study shows similar results

A smaller RCT of 92 patients that evaluated exacerbation rates with azithromycin and placebo recruited patients with at least 3 acute COPD exacerbations in the previous year.³

Compared with placebo, oral azithromycin 500 mg 3 times a week (Monday, Wednesday, and Friday) increased the time between exacerbations over a 12-month period (59 days vs 130 days; P=.001). It also reduced the exacerbation rate per person per year (1.94 vs 3.22; risk ratio=0.60; 95% CI, 0.43-0.84) but didn’t change the hospitalization rate (odds ratio=1.34; 95% CI, 0.67-2.7).

No difference in serious adverse events was found between the azithromycin and placebo groups (3 patients vs 5 patients; P=NS), but an increase in diarrhea (9 patients vs 1 patient; P=.015) was noted.

RECOMMENDATIONS

An evidence-based guideline by the American College of Chest Physicians and Canadian Thoracic Society recommends long-term macrolide therapy to prevent acute exacerbations in patients >40 years with moderate or severe COPD and a history of ≥1 moderate or severe exacerbation in the previous year despite maximized inhaler therapy (Grade 2A, weak recommendation, high-quality evidence).⁴ The guideline also states that the duration and optimal dosages are unknown.

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

EVIDENCE SUMMARY

A 2014 Cochrane meta-analysis of 5 RCTs with a total of 733 patients examined the effectiveness of any type of exercise in decreasing vasomotor symptoms in perimenopausal and postmenopausal women.¹ The studies compared exercise—defined as structured exercise or physical activity through active living—with no active treatment, yoga, or hormone therapy (HT) over a 3- to 24-month follow-up period.

Three trials of 454 women that compared exercise with no active treatment found no difference between groups in frequency or intensity of vasomotor symptoms (standard mean difference [SMD]= -0.10; 95% confidence interval [CI], -0.33 to 0.13).

Two trials with 279 women that compared exercise with yoga didn’t find a difference in reported frequency or intensity of vasomotor symptoms between the groups (SMD= -0.03; 95% CI, -0.45 to 0.38).

One small trial (14 women) of exercise and HT found that HT patients reported decreased frequency of flushes over 24 hours compared with the exercise group (mean difference [MD]=5.8; 95% CI, 3.17-8.43).

Overall, the evidence was of low quality because of heterogeneity in study design.¹

Two exercise interventions fail to reduce symptoms

A 2014 RCT, published after the Cochrane search date, investigated exercise as a treatment for VMS in 261 perimenopausal and postmenopausal women ages 48 to 57 years.² Patients had a history of at least 5 hot flashes or night sweats per day and hadn’t taken HT in the previous 3 months.

The women were randomized to one of 2 exercise interventions or a control group. The exercise interventions both entailed 2 one-on-one consultations with a physical activity facilitator and use of a pedometer. Patients were encouraged to perform 30 minutes of moderate-intensity exercise 3 days a week during Weeks 1 through 12, then increase the frequency to 3 to 5 days a week during Weeks 13 through 24. In one intervention arm, the women also received an informational DVD and 5 educational leaflets.

In the other arm, they were invited to attend 3 exercise support groups in their local community. The control group was offered an opportunity for exercise consultation and given a pedometer at the end of the study.

At the end of the 6-month intervention, neither exercise intervention significantly decreased self-reported hot flashes/night sweats per week compared with the control group (DVD exercise arm vs control: MD= -8.9; 95% CI, -20 to 2.2; social support exercise arm vs control: MD= -5.2; 95% CI, -16.7 to 6.3). The study also found no difference in hot flashes/night sweats per week at 12-month follow-up between the DVD exercise arm and controls (MD= -3.2; 95% CI, -12.7 to 6.4) and the social-support group and controls (MD= -3.5; 95% CI, -13.2 to 6.1).

Drug therapy relieves symptoms, but other methods—not so much

An analysis of pooled individual data from 3 RCTs compared exercise with 5 other interventions for VMS in 899 perimenopausal and postmenopausal women.³ Patients had at least 14 bothersome symptoms per week.

Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms in perimenopausal and post-menopausal women.

The 6 interventions ranged from nonpharmacologic therapies, such as aerobic exercise and yoga, to pharmacologic treatments, including escitalopram 10 to 20 mg/d, venlafaxine 75 mg/d, oral estradiol (E2) 0.5 mg/d, and omega-3 supplementation 1.8 g/d. The primary outcome was a change in VMS frequency and bother as assessed by a symptom diary over the 4- to 12-week follow-up.

The analysis found a significant 6-week reduction in daily VMS frequency relative to placebo for escitalopram (MD= -1.4; 95% CI, -2.7 to -0.2), low-dose E2 (MD= -1.9; 95% CI, -2.9 to -0.9), and venlafaxine (MD= -1.3; 95% CI, -2.3 to -0.3). However, no difference in VMS frequency or bother was found with exercise (MD= -0.4; 95% CI, -1.1 to 0.3), yoga (MD= -0.6; 95% CI, -1.3 to 0.1), or omega-3 supplementation (MD= 0.2; 95% CI, -0.4 to 0.8).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) doesn’t offer specific recommendations regarding exercise as a treatment for symptoms of menopause. The 2014 ACOG guidelines for managing symptoms report that data don’t support phytoestrogens, supplements, or lifestyle modifications (Level B, based on limited or inconsistent evidence). ACOG recommends basic palliative measures such as drinking cool drinks and decreasing layers of clothing (Level B).⁴

The American Association of Clinical Endocrinologists’ recommendations don’t mention exercise as a menopause therapy.⁵

The North American Menopause Society’s 2015 statement regarding the nonhormonal treatment of menopause symptoms doesn’t recommend exercise as an effective therapy because of insufficient or inconclusive data.⁶

EVIDENCE SUMMARY

A 2014 Cochrane meta-analysis of 5 RCTs with a total of 733 patients examined the effectiveness of any type of exercise in decreasing vasomotor symptoms in perimenopausal and postmenopausal women.¹ The studies compared exercise—defined as structured exercise or physical activity through active living—with no active treatment, yoga, or hormone therapy (HT) over a 3- to 24-month follow-up period.

Three trials of 454 women that compared exercise with no active treatment found no difference between groups in frequency or intensity of vasomotor symptoms (standard mean difference [SMD]= -0.10; 95% confidence interval [CI], -0.33 to 0.13).

Two trials with 279 women that compared exercise with yoga didn’t find a difference in reported frequency or intensity of vasomotor symptoms between the groups (SMD= -0.03; 95% CI, -0.45 to 0.38).

One small trial (14 women) of exercise and HT found that HT patients reported decreased frequency of flushes over 24 hours compared with the exercise group (mean difference [MD]=5.8; 95% CI, 3.17-8.43).

Overall, the evidence was of low quality because of heterogeneity in study design.¹

Two exercise interventions fail to reduce symptoms

A 2014 RCT, published after the Cochrane search date, investigated exercise as a treatment for VMS in 261 perimenopausal and postmenopausal women ages 48 to 57 years.² Patients had a history of at least 5 hot flashes or night sweats per day and hadn’t taken HT in the previous 3 months.

The women were randomized to one of 2 exercise interventions or a control group. The exercise interventions both entailed 2 one-on-one consultations with a physical activity facilitator and use of a pedometer. Patients were encouraged to perform 30 minutes of moderate-intensity exercise 3 days a week during Weeks 1 through 12, then increase the frequency to 3 to 5 days a week during Weeks 13 through 24. In one intervention arm, the women also received an informational DVD and 5 educational leaflets.

In the other arm, they were invited to attend 3 exercise support groups in their local community. The control group was offered an opportunity for exercise consultation and given a pedometer at the end of the study.

At the end of the 6-month intervention, neither exercise intervention significantly decreased self-reported hot flashes/night sweats per week compared with the control group (DVD exercise arm vs control: MD= -8.9; 95% CI, -20 to 2.2; social support exercise arm vs control: MD= -5.2; 95% CI, -16.7 to 6.3). The study also found no difference in hot flashes/night sweats per week at 12-month follow-up between the DVD exercise arm and controls (MD= -3.2; 95% CI, -12.7 to 6.4) and the social-support group and controls (MD= -3.5; 95% CI, -13.2 to 6.1).

Drug therapy relieves symptoms, but other methods—not so much

An analysis of pooled individual data from 3 RCTs compared exercise with 5 other interventions for VMS in 899 perimenopausal and postmenopausal women.³ Patients had at least 14 bothersome symptoms per week.

Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms in perimenopausal and post-menopausal women.

The 6 interventions ranged from nonpharmacologic therapies, such as aerobic exercise and yoga, to pharmacologic treatments, including escitalopram 10 to 20 mg/d, venlafaxine 75 mg/d, oral estradiol (E2) 0.5 mg/d, and omega-3 supplementation 1.8 g/d. The primary outcome was a change in VMS frequency and bother as assessed by a symptom diary over the 4- to 12-week follow-up.

The analysis found a significant 6-week reduction in daily VMS frequency relative to placebo for escitalopram (MD= -1.4; 95% CI, -2.7 to -0.2), low-dose E2 (MD= -1.9; 95% CI, -2.9 to -0.9), and venlafaxine (MD= -1.3; 95% CI, -2.3 to -0.3). However, no difference in VMS frequency or bother was found with exercise (MD= -0.4; 95% CI, -1.1 to 0.3), yoga (MD= -0.6; 95% CI, -1.3 to 0.1), or omega-3 supplementation (MD= 0.2; 95% CI, -0.4 to 0.8).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) doesn’t offer specific recommendations regarding exercise as a treatment for symptoms of menopause. The 2014 ACOG guidelines for managing symptoms report that data don’t support phytoestrogens, supplements, or lifestyle modifications (Level B, based on limited or inconsistent evidence). ACOG recommends basic palliative measures such as drinking cool drinks and decreasing layers of clothing (Level B).⁴

The American Association of Clinical Endocrinologists’ recommendations don’t mention exercise as a menopause therapy.⁵

The North American Menopause Society’s 2015 statement regarding the nonhormonal treatment of menopause symptoms doesn’t recommend exercise as an effective therapy because of insufficient or inconclusive data.⁶

EVIDENCE SUMMARY

A 2014 Cochrane meta-analysis of 5 RCTs with a total of 733 patients examined the effectiveness of any type of exercise in decreasing vasomotor symptoms in perimenopausal and postmenopausal women.¹ The studies compared exercise—defined as structured exercise or physical activity through active living—with no active treatment, yoga, or hormone therapy (HT) over a 3- to 24-month follow-up period.

Three trials of 454 women that compared exercise with no active treatment found no difference between groups in frequency or intensity of vasomotor symptoms (standard mean difference [SMD]= -0.10; 95% confidence interval [CI], -0.33 to 0.13).

Two trials with 279 women that compared exercise with yoga didn’t find a difference in reported frequency or intensity of vasomotor symptoms between the groups (SMD= -0.03; 95% CI, -0.45 to 0.38).

One small trial (14 women) of exercise and HT found that HT patients reported decreased frequency of flushes over 24 hours compared with the exercise group (mean difference [MD]=5.8; 95% CI, 3.17-8.43).

Overall, the evidence was of low quality because of heterogeneity in study design.¹

Two exercise interventions fail to reduce symptoms

A 2014 RCT, published after the Cochrane search date, investigated exercise as a treatment for VMS in 261 perimenopausal and postmenopausal women ages 48 to 57 years.² Patients had a history of at least 5 hot flashes or night sweats per day and hadn’t taken HT in the previous 3 months.

The women were randomized to one of 2 exercise interventions or a control group. The exercise interventions both entailed 2 one-on-one consultations with a physical activity facilitator and use of a pedometer. Patients were encouraged to perform 30 minutes of moderate-intensity exercise 3 days a week during Weeks 1 through 12, then increase the frequency to 3 to 5 days a week during Weeks 13 through 24. In one intervention arm, the women also received an informational DVD and 5 educational leaflets.

In the other arm, they were invited to attend 3 exercise support groups in their local community. The control group was offered an opportunity for exercise consultation and given a pedometer at the end of the study.

At the end of the 6-month intervention, neither exercise intervention significantly decreased self-reported hot flashes/night sweats per week compared with the control group (DVD exercise arm vs control: MD= -8.9; 95% CI, -20 to 2.2; social support exercise arm vs control: MD= -5.2; 95% CI, -16.7 to 6.3). The study also found no difference in hot flashes/night sweats per week at 12-month follow-up between the DVD exercise arm and controls (MD= -3.2; 95% CI, -12.7 to 6.4) and the social-support group and controls (MD= -3.5; 95% CI, -13.2 to 6.1).

Drug therapy relieves symptoms, but other methods—not so much

An analysis of pooled individual data from 3 RCTs compared exercise with 5 other interventions for VMS in 899 perimenopausal and postmenopausal women.³ Patients had at least 14 bothersome symptoms per week.

Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms in perimenopausal and post-menopausal women.

The 6 interventions ranged from nonpharmacologic therapies, such as aerobic exercise and yoga, to pharmacologic treatments, including escitalopram 10 to 20 mg/d, venlafaxine 75 mg/d, oral estradiol (E2) 0.5 mg/d, and omega-3 supplementation 1.8 g/d. The primary outcome was a change in VMS frequency and bother as assessed by a symptom diary over the 4- to 12-week follow-up.

The analysis found a significant 6-week reduction in daily VMS frequency relative to placebo for escitalopram (MD= -1.4; 95% CI, -2.7 to -0.2), low-dose E2 (MD= -1.9; 95% CI, -2.9 to -0.9), and venlafaxine (MD= -1.3; 95% CI, -2.3 to -0.3). However, no difference in VMS frequency or bother was found with exercise (MD= -0.4; 95% CI, -1.1 to 0.3), yoga (MD= -0.6; 95% CI, -1.3 to 0.1), or omega-3 supplementation (MD= 0.2; 95% CI, -0.4 to 0.8).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) doesn’t offer specific recommendations regarding exercise as a treatment for symptoms of menopause. The 2014 ACOG guidelines for managing symptoms report that data don’t support phytoestrogens, supplements, or lifestyle modifications (Level B, based on limited or inconsistent evidence). ACOG recommends basic palliative measures such as drinking cool drinks and decreasing layers of clothing (Level B).⁴

The American Association of Clinical Endocrinologists’ recommendations don’t mention exercise as a menopause therapy.⁵

The North American Menopause Society’s 2015 statement regarding the nonhormonal treatment of menopause symptoms doesn’t recommend exercise as an effective therapy because of insufficient or inconclusive data.⁶

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

A 54-year-old man presents to the emergency department (ED) with acute-onset left flank pain that radiates to the groin. CT of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed an appropriate candidate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8%, with a self-reported prevalence of 10.6% in men and 7.1% in women.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with NSAIDs as firstline treatment and opioids as a second-line option.³

In addition, α-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the α-blocker tamsulosin. Two systematic reviews (limited by heterogeneity because some of the studies lacked a placebo control and blinding) concluded that α-blockers increased stone passage within one to six weeks when compared with placebo or no additional therapy.^4,5 However, a recent large, multicenter RCT revealed no difference between tamsulosin and nifedipine, or either one compared with placebo, at decreasing the need for further treatment to achieve stone passage within four weeks.⁶

STUDY SUMMARY

Results broken down by stone size

This meta-analysis, comprising eight double-blind RCTs, examined the effect of oral tamsulosin (0.4 mg/d; average course, 28 d) on distal ureteral stone passage in adult patients (N = 1,384).¹ A subgroup analysis comparing stone size (< 5 mm and 5-10 mm) was also conducted to determine whether size modified the effect of tamsulosin.

The eight selected studies were published between 2009 and 2015; the trials were conducted in multiple countries, in ED and outpatient urology settings. The main outcome measure was the risk difference (RD) in stone passage between the tamsulosin group and placebo group after follow-up imaging at three weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk for stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; RD, 17%), but significant heterogeneity existed across the trials (I², 80.2%). Subgroup analysis by stone size (< 5 mm vs 5-10 mm) revealed that, compared to placebo, tamsulosin was beneficial for larger stones (6 trials, N = 514; RD, 22%; number needed to treat, 5) but not for smaller stones (4 trials, N = 533; RD, –0.3%). The 5-to-10–mm subgroup had a less heterogeneous population of studies than did the < 5-mm subgroup (I², 33% and 0% respectively).

In terms of adverse events, tamsulosin did not increase the risk for dizziness (RD, 0.2%) or postural hypotension (RD, 0.1%), compared with placebo.

WHAT’S NEW

Increased passage of larger stones

This meta-analysis included only double-blind RCTs; prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Clinician Reviews. 2016;26[4]:20,44), which recommended against the use of α-blockers tamsulosin and nifedipine for ureteral stones measuring < 10 mm.^6,7

But the subgroup analysis in this review went one step further by examining passage rates by stone size (< 5 mm vs 5-10 mm) and revealing that passage of larger stones increased with tamsulosin use. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

What about proximal or XL stones?

Only distal stones were included in seven of the eight trials in this analysis. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones > 10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018; 67[1]:37-38).

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A 2015 network meta-analysis of 137 RCTs with 33,243 patients (ages 45-76 years) with knee OA compared the effectiveness of a variety of treatments including intra-articular CS and HA.¹ At 3 months, the effect on pain was not significantly different between the CS and HA groups (12 trials; effect size [ES]=0.02; 95% confidence interval [CI], -0.12 to 0.17). However, a small but significant improvement in function was noted (scoring system not defined) at 3 months favoring HA (ES=0.24; 95% CI, 0.06-0.43; number of trials not specified).

At 3 and 6 months, HA improves pain, but not function, more than CS

Another meta-analysis published in 2015 examined the effectiveness of intra-articular CS and HA in 7 RCTs with 583 patients with knee OA.² All 7 trials were included in the network meta-analysis and discussed separately to evaluate different time points.

Pain at one month wasn’t significantly different using a visual analog score (VAS) of one to 100 (4 trials; 245 patients; mean difference [MD]=1.66 points; 95% CI, -0.90 to 4.23). At 3 and 6 months, the HA group reported significantly reduced pain compared with the CS group (3 months: 3 trials; 320 patients; MD=12.58 points; 95% CI, -17.76 to -7.40; 6 months: 5 trials; 411 patients; MD=9.01 points; 95% CI, -12.62 to -5.40). There were no significant differences in function outcomes (Index of severity for OA of the knee by Lequesne et al; The Knee Society Clinical Rating System), maximum flexion, or adverse events.

Triamcinolone improves pain, function, but not for long

A 2016 double-blind RCT of 110 patients with knee OA compared intra-articular HA and triamcinolone, assessing pain and function at intervals between 24 hours and 6 months.³ Patients in the HA group received a single injection of 6 mL hylan G-F 20 (Synvisc); patients in the CS group received 1 mL of triamcinolone acetonide 40 mg and 5 mL of 1% lidocaine with epinephrine.

The CS group reported significantly less pain (VAS score 1 to 100) at 24 hours than the HA group (24 points vs 36 points; P=.002); relief lasted as long as one week (14 points vs 23 points; P=.018). After the first week, no difference was seen in pain between groups for as long as 6 months.

Function, assessed by a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 1 to 100; higher score indicates worse pain, stiffness, and function) showed a significant improvement with CS at 2 weeks (25 points vs 31 points; P=.03), but no difference at any other time point up to 6 months.

A 2015 RCT of 200 patients with knee OA compared the effectiveness of intra-articular HA and betamethasone.⁴ Evaluators were blinded and assessments were made at 3, 6, 9, and 12 months. The HA group received 2.5 mL of 1% HA (Suprahyal); the CS group received betamethasone dipropionate 5 mg plus betamethasone sodium phosphate 2 mg in 1 mL.

Inconsistent evidence shows a small amount of pain relief at one week to 3 months with corticosteroid injections.

The CS group had significantly less pain (VAS 1 to 10) at 3 months compared with the HA group (2.2 points vs 3.1 points; P=.004), but the HA group had less pain at all other time points (6 months: 3.9 points vs 2.4 points; P=.0001; 9 months: 5.5 points vs 3.6 points; P=.0001; 12 months: 6 points vs 4.1 points; P=.0001).

The WOMAC function subscores (0 to 68; lower indicates more function) were significantly better at all follow-up points in the HA group compared with the CS group (3 months: 19 vs 25; P=.0001; 6 months: 17 vs 29; P=.0001; 9 months: 25 vs 42; P=.0001; 12 months: 28 vs 42; P=.0001).⁴

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons 2013 work group couldn’t recommend for or against using intra-articular CS for patients with symptomatic knee OA based on inconclusive evidence.⁵ They also couldn’t recommend using HA (SOR: strong).

The National Institute for Health and Care Excellence (NICE) stated in 2008 that intra-articular CS injections should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with OA.⁶ In 2014, NICE recommended against offering intra-articular HA injections for managing OA.

The US Veterans Administration and Department of Defense have issued guidelines stating that clinicians may consider intra-articular CS injections for patients with symptomatic knee OA (US Preventive Services Task Force [USPSTF] Grade B).⁷ They report insufficient evidence to recommend for or against the use of intra-articular HA with the caveat that HA may be considered for patients who don’t respond adequately to nonpharmacologic measures and who have an inadequate response, intolerable adverse events, or contraindications to other pharmacologic therapies (USPSTF Grade I).

EVIDENCE SUMMARY

A 2015 network meta-analysis of 137 RCTs with 33,243 patients (ages 45-76 years) with knee OA compared the effectiveness of a variety of treatments including intra-articular CS and HA.¹ At 3 months, the effect on pain was not significantly different between the CS and HA groups (12 trials; effect size [ES]=0.02; 95% confidence interval [CI], -0.12 to 0.17). However, a small but significant improvement in function was noted (scoring system not defined) at 3 months favoring HA (ES=0.24; 95% CI, 0.06-0.43; number of trials not specified).

At 3 and 6 months, HA improves pain, but not function, more than CS

Another meta-analysis published in 2015 examined the effectiveness of intra-articular CS and HA in 7 RCTs with 583 patients with knee OA.² All 7 trials were included in the network meta-analysis and discussed separately to evaluate different time points.

Pain at one month wasn’t significantly different using a visual analog score (VAS) of one to 100 (4 trials; 245 patients; mean difference [MD]=1.66 points; 95% CI, -0.90 to 4.23). At 3 and 6 months, the HA group reported significantly reduced pain compared with the CS group (3 months: 3 trials; 320 patients; MD=12.58 points; 95% CI, -17.76 to -7.40; 6 months: 5 trials; 411 patients; MD=9.01 points; 95% CI, -12.62 to -5.40). There were no significant differences in function outcomes (Index of severity for OA of the knee by Lequesne et al; The Knee Society Clinical Rating System), maximum flexion, or adverse events.

Triamcinolone improves pain, function, but not for long

A 2016 double-blind RCT of 110 patients with knee OA compared intra-articular HA and triamcinolone, assessing pain and function at intervals between 24 hours and 6 months.³ Patients in the HA group received a single injection of 6 mL hylan G-F 20 (Synvisc); patients in the CS group received 1 mL of triamcinolone acetonide 40 mg and 5 mL of 1% lidocaine with epinephrine.

The CS group reported significantly less pain (VAS score 1 to 100) at 24 hours than the HA group (24 points vs 36 points; P=.002); relief lasted as long as one week (14 points vs 23 points; P=.018). After the first week, no difference was seen in pain between groups for as long as 6 months.

Function, assessed by a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 1 to 100; higher score indicates worse pain, stiffness, and function) showed a significant improvement with CS at 2 weeks (25 points vs 31 points; P=.03), but no difference at any other time point up to 6 months.

A 2015 RCT of 200 patients with knee OA compared the effectiveness of intra-articular HA and betamethasone.⁴ Evaluators were blinded and assessments were made at 3, 6, 9, and 12 months. The HA group received 2.5 mL of 1% HA (Suprahyal); the CS group received betamethasone dipropionate 5 mg plus betamethasone sodium phosphate 2 mg in 1 mL.

Inconsistent evidence shows a small amount of pain relief at one week to 3 months with corticosteroid injections.

The CS group had significantly less pain (VAS 1 to 10) at 3 months compared with the HA group (2.2 points vs 3.1 points; P=.004), but the HA group had less pain at all other time points (6 months: 3.9 points vs 2.4 points; P=.0001; 9 months: 5.5 points vs 3.6 points; P=.0001; 12 months: 6 points vs 4.1 points; P=.0001).

The WOMAC function subscores (0 to 68; lower indicates more function) were significantly better at all follow-up points in the HA group compared with the CS group (3 months: 19 vs 25; P=.0001; 6 months: 17 vs 29; P=.0001; 9 months: 25 vs 42; P=.0001; 12 months: 28 vs 42; P=.0001).⁴

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons 2013 work group couldn’t recommend for or against using intra-articular CS for patients with symptomatic knee OA based on inconclusive evidence.⁵ They also couldn’t recommend using HA (SOR: strong).

The National Institute for Health and Care Excellence (NICE) stated in 2008 that intra-articular CS injections should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with OA.⁶ In 2014, NICE recommended against offering intra-articular HA injections for managing OA.

The US Veterans Administration and Department of Defense have issued guidelines stating that clinicians may consider intra-articular CS injections for patients with symptomatic knee OA (US Preventive Services Task Force [USPSTF] Grade B).⁷ They report insufficient evidence to recommend for or against the use of intra-articular HA with the caveat that HA may be considered for patients who don’t respond adequately to nonpharmacologic measures and who have an inadequate response, intolerable adverse events, or contraindications to other pharmacologic therapies (USPSTF Grade I).

EVIDENCE SUMMARY

A 2015 network meta-analysis of 137 RCTs with 33,243 patients (ages 45-76 years) with knee OA compared the effectiveness of a variety of treatments including intra-articular CS and HA.¹ At 3 months, the effect on pain was not significantly different between the CS and HA groups (12 trials; effect size [ES]=0.02; 95% confidence interval [CI], -0.12 to 0.17). However, a small but significant improvement in function was noted (scoring system not defined) at 3 months favoring HA (ES=0.24; 95% CI, 0.06-0.43; number of trials not specified).

At 3 and 6 months, HA improves pain, but not function, more than CS

Another meta-analysis published in 2015 examined the effectiveness of intra-articular CS and HA in 7 RCTs with 583 patients with knee OA.² All 7 trials were included in the network meta-analysis and discussed separately to evaluate different time points.

Pain at one month wasn’t significantly different using a visual analog score (VAS) of one to 100 (4 trials; 245 patients; mean difference [MD]=1.66 points; 95% CI, -0.90 to 4.23). At 3 and 6 months, the HA group reported significantly reduced pain compared with the CS group (3 months: 3 trials; 320 patients; MD=12.58 points; 95% CI, -17.76 to -7.40; 6 months: 5 trials; 411 patients; MD=9.01 points; 95% CI, -12.62 to -5.40). There were no significant differences in function outcomes (Index of severity for OA of the knee by Lequesne et al; The Knee Society Clinical Rating System), maximum flexion, or adverse events.

Triamcinolone improves pain, function, but not for long

A 2016 double-blind RCT of 110 patients with knee OA compared intra-articular HA and triamcinolone, assessing pain and function at intervals between 24 hours and 6 months.³ Patients in the HA group received a single injection of 6 mL hylan G-F 20 (Synvisc); patients in the CS group received 1 mL of triamcinolone acetonide 40 mg and 5 mL of 1% lidocaine with epinephrine.

The CS group reported significantly less pain (VAS score 1 to 100) at 24 hours than the HA group (24 points vs 36 points; P=.002); relief lasted as long as one week (14 points vs 23 points; P=.018). After the first week, no difference was seen in pain between groups for as long as 6 months.

Function, assessed by a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 1 to 100; higher score indicates worse pain, stiffness, and function) showed a significant improvement with CS at 2 weeks (25 points vs 31 points; P=.03), but no difference at any other time point up to 6 months.

A 2015 RCT of 200 patients with knee OA compared the effectiveness of intra-articular HA and betamethasone.⁴ Evaluators were blinded and assessments were made at 3, 6, 9, and 12 months. The HA group received 2.5 mL of 1% HA (Suprahyal); the CS group received betamethasone dipropionate 5 mg plus betamethasone sodium phosphate 2 mg in 1 mL.

Inconsistent evidence shows a small amount of pain relief at one week to 3 months with corticosteroid injections.

The CS group had significantly less pain (VAS 1 to 10) at 3 months compared with the HA group (2.2 points vs 3.1 points; P=.004), but the HA group had less pain at all other time points (6 months: 3.9 points vs 2.4 points; P=.0001; 9 months: 5.5 points vs 3.6 points; P=.0001; 12 months: 6 points vs 4.1 points; P=.0001).

The WOMAC function subscores (0 to 68; lower indicates more function) were significantly better at all follow-up points in the HA group compared with the CS group (3 months: 19 vs 25; P=.0001; 6 months: 17 vs 29; P=.0001; 9 months: 25 vs 42; P=.0001; 12 months: 28 vs 42; P=.0001).⁴

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons 2013 work group couldn’t recommend for or against using intra-articular CS for patients with symptomatic knee OA based on inconclusive evidence.⁵ They also couldn’t recommend using HA (SOR: strong).

The National Institute for Health and Care Excellence (NICE) stated in 2008 that intra-articular CS injections should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with OA.⁶ In 2014, NICE recommended against offering intra-articular HA injections for managing OA.

The US Veterans Administration and Department of Defense have issued guidelines stating that clinicians may consider intra-articular CS injections for patients with symptomatic knee OA (US Preventive Services Task Force [USPSTF] Grade B).⁷ They report insufficient evidence to recommend for or against the use of intra-articular HA with the caveat that HA may be considered for patients who don’t respond adequately to nonpharmacologic measures and who have an inadequate response, intolerable adverse events, or contraindications to other pharmacologic therapies (USPSTF Grade I).

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

ILLUSTRATIVE CASE

A 66-year-old man with a history of hypertension and diabetes mellitus type 2 is hospitalized for palpitations and dizziness, and is given a diagnosis of atrial fibrillation (AF). His heart rate is successfully controlled with a beta-blocker. His CHA₂DS₂-VASc score is 3, meaning he is a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with AF results in stroke and death and can be decreased with appropriate use of antithrombotic therapy. Evidence-based guidelines recommend patients with AF at intermediate or high risk of stroke (CHADS₂ score ≥ 2 or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends the use of the direct oral anticoagulant (DOAC) dabigatran over warfarin for those patients with nonvalvular AF with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) of individual DOACs (dabigatran [a direct thrombin inhibitor], rivaroxaban, apixaban, and edoxaban [factor Xa inhibitors]) revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk=1.25; 95% CI, 1.01 to 1.55) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, 3 separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications result in a significant reduction in embolic stroke and reduced the risk of major bleeds and hemorrhagic stroke when compared with warfarin.^5-7

Rivaroxaban may be more effective than warfarin at preventing ischemic stroke and systemic emboli, and apixaban and dabigatran have a lower risk of bleeding.

However, we know less about the comparative effectiveness and safety of the DOACs when they are used in clinical practice, and it is not clear which, if any of these agents, are superior to others. Moreover, only about half of the patients in the United States with AF who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

One DOAC is better than warfarin at one thing; 2 others are better at another

This large cohort study examined the effectiveness of 3 DOACs compared with warfarin in 61,678 patients with AF by combining data from 3 Danish national databases. The patients had newly diagnosed AF (without valvular disease or venous thromboembolism) and were prescribed standard doses of DOACs (dabigatran 150 bid [N=12,701], rivaroxaban 20 mg/d [N=7192], apixaban 5 mg bid [N=6349]) or dose-adjusted warfarin to an INR goal of 2 to 3 (N=35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1702 ischemic strokes or systemic emboli. The incidence of ischemic stroke or systemic embolism was either the same or better for each of the 3 DOAC treatments than for warfarin (DOACs, 2.9-3.9 events per 100 person-years; warfarin, 3.3 events per 100 person-years; no P value provided). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group compared with warfarin at one year (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.69-0.99) and after 2.5 years (HR=0.80; 95% CI, 0.69-0.94). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at one year and 2.5 years.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR=0.63; 95% CI, 0.53-0.76) and dabigatran group (HR=0.61; 95% CI, 0.51-0.74) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk of death. Compared with warfarin, the risk of death after one year of treatment was lower in the apixaban (HR=0.65; 95% CI, 0.56-0.75) and dabigatran (HR=0.63; 95% CI, 0.48-0.82) groups, and there was no significant difference in the rivaroxaban group (HR=0.92; 95% CI, 0.82-1.03).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, and that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk of bleeding than warfarin.

CAVEATS

This non-randomized cohort trial lacked INR data

This study was a non-randomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin was not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. We feel that this study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 66-year-old man with a history of hypertension and diabetes mellitus type 2 is hospitalized for palpitations and dizziness, and is given a diagnosis of atrial fibrillation (AF). His heart rate is successfully controlled with a beta-blocker. His CHA₂DS₂-VASc score is 3, meaning he is a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with AF results in stroke and death and can be decreased with appropriate use of antithrombotic therapy. Evidence-based guidelines recommend patients with AF at intermediate or high risk of stroke (CHADS₂ score ≥ 2 or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends the use of the direct oral anticoagulant (DOAC) dabigatran over warfarin for those patients with nonvalvular AF with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) of individual DOACs (dabigatran [a direct thrombin inhibitor], rivaroxaban, apixaban, and edoxaban [factor Xa inhibitors]) revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk=1.25; 95% CI, 1.01 to 1.55) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, 3 separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications result in a significant reduction in embolic stroke and reduced the risk of major bleeds and hemorrhagic stroke when compared with warfarin.^5-7

Rivaroxaban may be more effective than warfarin at preventing ischemic stroke and systemic emboli, and apixaban and dabigatran have a lower risk of bleeding.

However, we know less about the comparative effectiveness and safety of the DOACs when they are used in clinical practice, and it is not clear which, if any of these agents, are superior to others. Moreover, only about half of the patients in the United States with AF who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

One DOAC is better than warfarin at one thing; 2 others are better at another

This large cohort study examined the effectiveness of 3 DOACs compared with warfarin in 61,678 patients with AF by combining data from 3 Danish national databases. The patients had newly diagnosed AF (without valvular disease or venous thromboembolism) and were prescribed standard doses of DOACs (dabigatran 150 bid [N=12,701], rivaroxaban 20 mg/d [N=7192], apixaban 5 mg bid [N=6349]) or dose-adjusted warfarin to an INR goal of 2 to 3 (N=35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1702 ischemic strokes or systemic emboli. The incidence of ischemic stroke or systemic embolism was either the same or better for each of the 3 DOAC treatments than for warfarin (DOACs, 2.9-3.9 events per 100 person-years; warfarin, 3.3 events per 100 person-years; no P value provided). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group compared with warfarin at one year (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.69-0.99) and after 2.5 years (HR=0.80; 95% CI, 0.69-0.94). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at one year and 2.5 years.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR=0.63; 95% CI, 0.53-0.76) and dabigatran group (HR=0.61; 95% CI, 0.51-0.74) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk of death. Compared with warfarin, the risk of death after one year of treatment was lower in the apixaban (HR=0.65; 95% CI, 0.56-0.75) and dabigatran (HR=0.63; 95% CI, 0.48-0.82) groups, and there was no significant difference in the rivaroxaban group (HR=0.92; 95% CI, 0.82-1.03).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, and that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk of bleeding than warfarin.

CAVEATS

This non-randomized cohort trial lacked INR data

This study was a non-randomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin was not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. We feel that this study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 66-year-old man with a history of hypertension and diabetes mellitus type 2 is hospitalized for palpitations and dizziness, and is given a diagnosis of atrial fibrillation (AF). His heart rate is successfully controlled with a beta-blocker. His CHA₂DS₂-VASc score is 3, meaning he is a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with AF results in stroke and death and can be decreased with appropriate use of antithrombotic therapy. Evidence-based guidelines recommend patients with AF at intermediate or high risk of stroke (CHADS₂ score ≥ 2 or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends the use of the direct oral anticoagulant (DOAC) dabigatran over warfarin for those patients with nonvalvular AF with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) of individual DOACs (dabigatran [a direct thrombin inhibitor], rivaroxaban, apixaban, and edoxaban [factor Xa inhibitors]) revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk=1.25; 95% CI, 1.01 to 1.55) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, 3 separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications result in a significant reduction in embolic stroke and reduced the risk of major bleeds and hemorrhagic stroke when compared with warfarin.^5-7

Rivaroxaban may be more effective than warfarin at preventing ischemic stroke and systemic emboli, and apixaban and dabigatran have a lower risk of bleeding.

However, we know less about the comparative effectiveness and safety of the DOACs when they are used in clinical practice, and it is not clear which, if any of these agents, are superior to others. Moreover, only about half of the patients in the United States with AF who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

One DOAC is better than warfarin at one thing; 2 others are better at another

This large cohort study examined the effectiveness of 3 DOACs compared with warfarin in 61,678 patients with AF by combining data from 3 Danish national databases. The patients had newly diagnosed AF (without valvular disease or venous thromboembolism) and were prescribed standard doses of DOACs (dabigatran 150 bid [N=12,701], rivaroxaban 20 mg/d [N=7192], apixaban 5 mg bid [N=6349]) or dose-adjusted warfarin to an INR goal of 2 to 3 (N=35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1702 ischemic strokes or systemic emboli. The incidence of ischemic stroke or systemic embolism was either the same or better for each of the 3 DOAC treatments than for warfarin (DOACs, 2.9-3.9 events per 100 person-years; warfarin, 3.3 events per 100 person-years; no P value provided). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group compared with warfarin at one year (hazard ratio [HR]=0.83; 95% confidence interval [CI], 0.69-0.99) and after 2.5 years (HR=0.80; 95% CI, 0.69-0.94). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at one year and 2.5 years.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR=0.63; 95% CI, 0.53-0.76) and dabigatran group (HR=0.61; 95% CI, 0.51-0.74) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk of death. Compared with warfarin, the risk of death after one year of treatment was lower in the apixaban (HR=0.65; 95% CI, 0.56-0.75) and dabigatran (HR=0.63; 95% CI, 0.48-0.82) groups, and there was no significant difference in the rivaroxaban group (HR=0.92; 95% CI, 0.82-1.03).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, and that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk of bleeding than warfarin.

CAVEATS

This non-randomized cohort trial lacked INR data

This study was a non-randomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin was not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. We feel that this study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.